Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

Abstract

Boron containing compounds have not been widely studied in Medicinal Chemistry, mainly due to the idea that this group could confer some toxicity. Nowadays, this concept has been demystified and, especially after the discovery of the drug bortezomib, the interest for these compounds, mainly boronic acids, has been growing. In this review, several activities of boronic acids, such as anticancer, antibacterial, antiviral activity, and even their application as sensors and delivery systems are addressed. The synthetic processes used to obtain these active compounds are also referred. Noteworthy, the molecular modification by the introduction of boronic acid group to bioactive molecules has shown to modify selectivity, physicochemical, and pharmacokinetic characteristics, with the improvement of the already existing activities. Besides, the preparation of compounds with this chemical group is relatively simple and well known. Taking into consideration these findings, this review reinforces the relevance of extending the studies with boronic acids in Medicinal Chemistry, in order to obtain new promising drugs shortly.

Keywords: biological applications; boron-containing compounds; boronic acids; synthesis of boronic acid derivatives.

Figure 1

Organoboron compounds.

Figure 2

Ionization equilibrium of boronic acid in aqueous solutions. (a) Boronic acid as Lewis acid. (b) Boronic acid as Brønsted–Lowry acid.

Figure 3

Drugs containing boronic acid approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). (a) Bortezomib. (b) Ixazomib. (c) Vaborbactam.

Figure 4

Molecular targets of boronic acids. Serine Proteases include: Dipeptidyl Peptidase IV (DPPIV), Factor Xa (fXa) and XIa, Hepatitis C Virus (HCV) NS3, Hormone-sensitive lipase (HSL), IgA1 protease, Pancreatic cholesterol esterase (CEase), Prostate specific antigen (PSA), Thrombin, α-Chymotrypsin, α-lytic protease, β-lactamases. Other enzymes include: Aminopeptidases, Arginase, human Carbonic anhydrase IX (hCA IX), hCA XII), Cysteine protease, Fatty Acid Amide Hydrolase (FAAH), Histone deacetylases (HDACs), HIV-1 Protease (HIV-1 PR), Leucyl-tRNA synthetase (LeuRS), RNA-dependent RNA polymerase NS5B (NS5B), Tyrosine Kinase DYRK1A (DYRK1A), Steroid sulfatase (STS), γ-Glutamyl transpeptidase (γ-GT), 3Clike protease (3CLpro). Proteins include: Murine double minute 2 (MDM2), NorA efflux pump (NorA), Penicillin binding protein 3 (PBP3), PBP4, PBP5, Transthyretin (TTR), 20S proteasome. Transcription factors include: Hypoxia-inducible factor 1-α (HIF 1-α). Receptors include: Chemokine receptors 1 (CXCR1), CXCR2, CXCL8, Epidermal growth factor receptor tyrosine kinase (EGFR-TK), Estrogen Receptor α (ERα).

Figure 5

Possible formation of a cyclic boronic acid derivative, when boronic acid is located next to an urea group.

Figure 6

Methotrexate and its phenylboronic acid prodrug (48 and 49, respectively).

Figure 7

Compound SM23 (72), an inhibitor of class C β-lactamases and of biofilms formation.

Figure 8

BPBA compound (81), disruptor of Rev-RRE interaction and inhibitor of HIV-1 replication.

Figure 9

NS5B polymerase inhibitor for HCV treatment (93) and its metabolites (94 and 95).

Figure 10

Boronic acid derivatives as sensors. 106: Poly(L- and D-lysine) with phenylboronic acid as a glucose sensor; 107: Boronic acid derivative with a fluorophore for saccharide sensing; 108: Poly(aniline boronic acid) polymer as a dopamine sensor; 109: Anthracene-based diboronic acid, an oligosaccharide sensor.

Figure 11

Examples of bioactive diazaborines. 110, compound with antibacterial activity; 111: Compound with anticancer activity.

Figure 12

Boronic esters as promising compounds in Medicinal Chemistry. 122: Selective proteasome inhibitor and apoptotic agent; 123: Antibacterial agent against E. coli, P. aeruginosa, K. pneumoniae, and S. aureus.

Figure 13

Biological applications and respective activities of boronic acid derivatives.

Scheme 1

Synthetic processes to obtain aryl boronic acids. (a) Electrophilic trapping of arylmetal intermediates with borate esters from aryl halides using Grignard reagents or through lithium–halogen exchange, respectively. (b) Coupling of aryl halides with diboronic acid reagents. (c) Direct boronylation by transition metal-catalyzed aromatic C–H functionalization. (d) Bromide–lithium exchange reaction through flow chemistry. (e) Transmetallation of aryl silanes and stannanes.

Scheme 2

Synthesis of the chalcone-boronic acid compounds 2–5. Reaction conditions: (i) KOH, MeOH, reflux, 0 °C to room temperature (r.t.), 55 min; (ii) (1) NaH, pinacol (bromomethyl)boronate, THF, 0 °C to r.t., overnight; (2) NaOH, H₂O.

Scheme 3

Synthesis of the chalcone-diboronic acid compound 8. Reaction conditions: (i) KOH, EtOH, H₂O, 0 °C to r.t., overnight.

Scheme 4

Synthesis of the dipeptide boronic acids 15–17, and of the prodrug 18. Reaction conditions: (i) R₁COOH, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazol (HOBt), N,N-diisopropylethylamine (DIPEA), CH₂Cl₂, −10 °C to r.t.; (ii) (1) LiOH·H₂O, MeOH, H₂O, r.t.; (2) 1 N HCl, EtOAc, r.t.; (iii) EDCI, HOBt, DIPEA, CH₂Cl₂, −10 °C to r.t.; (iv) 1 N HCl, MeOH, n-hexane, r.t., 22 h; (v) EtOAc, diethanolamine (DEA), 74 °C to r.t., overnight.

Scheme 5

Synthesis of the urea-peptide boronic acid 25. Reaction conditions: (i) CDI, dimethylformamide (DMF), MeCN, r.t.; (ii) (1) NaOH, 0 °C; (2) HCl, 0 °C; (iii) N,N′-dicyclohexylcarbodiimide (DCC), HOBt, DIPEA, CH₂Cl₂, r.t. (iv) (1) DEA, EtOAc, r.t.; (2) HCl, H₂O, EtOAc, r.t., 2 h.

Scheme 6

Synthesis of the cis (32) and trans-boronic acid (33) analogues based on the antimitotic agent CA-4. Reaction conditions: (i) NaBH₄, MeOH, H₂O, EtOAc, r.t., 30 min; (ii) PBr₃, CH₂Cl₂, 0 °C to r.t., overnight; (iii) PPh₃, THF, r.t., 6 h; (iv) 3-bromo-4-methoxybenzaldehyde, sodium bis(trimethylsilyl)amide (NaHMDS), THF, −78 °C to r.t., 6.5 h; (v) (1) 5% EtOAc/n-hexane, column chromatography; (2) n-BuLi, B(OMe)₃, THF, −78 °C to r.t., overnight; (3) 3N HCl, r.t., 30 min.

Scheme 7

Synthesis of the chalcone-boronic acid analogue 36. Reaction conditions: (i) (1) 1-(3,4,5-trimethoxyphenyl)ethenone, 5-formyl-2-methoxyboronic acid, NaOH, r.t., overnight; (2) H₂O, HCl.

Scheme 8

Synthesis of the chalcone-boronic acid analogue 38. Reaction conditions: (i) CH₂Cl₂, AlCl₃, acetic anhydride, r.t. to 40 °C, 1 h; (ii) Ethylene glycol, benzene, reflux, PTSA; (iii) (1) THF, n-BuLi, B(OMe)₃, −78 °C, 90 min; (2) HCl, r.t., 30 min; (iv) (1) 3,4,5-trimethoxybenzaldehyde, NaOH, r.t., overnight; (2) H₂O, HCl.

Scheme 9

Synthesis of a SERD boronic acid analogue 43 based on the drug fulvestrant. Reaction conditions: (i) Triflic anhydride, pyridine, CH₂Cl₂, −10 °C; (ii) B₂pin₂, palladium(II) acetate (Pd(OAc)₂), tricyclohexylphosphine, MeCN, 80 °C; (iii) KOH, MeOH/THF, 0 °C to r.t., 4 h; (iv) mCPBA, CH₂Cl₂, 0 °C.

Scheme 10

Synthesis of the camptothecin prodrug with boronic acid moiety (47). Reaction conditions (i) N,N-bis(trifluoromethylsulfonyl)aniline, triethylamine (TEA), DMF, 60 °C, 3 h; (ii) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl₂), KOAc, B₂pin₂, 1,4-dioxane, 80 °C, 12 h; (iii) NaIO₄, NH₄OAc, 1:1 C₃H₆O:H₂O, r.t., 24 h.

Scheme 11

Synthesis of the crizotinib prodrugs with boronic acid moiety 51 and 52. Reaction conditions: (i) Di-tert-butyl dicarbonate, THF, 12 h; (ii) (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol, CO, Pd(OAc)₂, copper(II) acetate monohydrate (Cu(OAc)₂∙H₂O), KI, DMSO, MeCN; (iii) TFA, CH₂Cl₂, r.t., 2 h (51) or 30 min (52); (iv) 4-hydroxybenzaldehyde, 2-picoline borane, AcOH/MeOH, overnight.

Scheme 12

Synthesis of the boronic acid autotaxin inhibitor 55. Reaction conditions: (i) NaH, DMF, 1-(chloromethyl)-4-fluorobenzene, r.t., 22 h; (ii) B₂pin₂, Pd(dppf)Cl₂, KOAc, DMF, 80 °C, 18 h; (iii) THF, NaIO₄, HCl; (iv) EtOH, piperidine, 22 h, reflux.

Scheme 13

Synthesis of the boronic acids HDAC inhibitors 59–61. Reaction conditions: (i) (Boc)₂O, TEA, THF, r.t.; (ii) NaOEt, 5-Bromopent-1-ene, EtOH, reflux; (iii) LiOH·H₂O, EtOH, H₂O, 0 °C; (iv) toluene, reflux; (v) 3-Biphenyl-NH₂, EDCI, HOBt·H₂O, DMF, r.t.; (vi) cyclooctadiene iridium chloride dimer ([Ir(cod)Cl]₂), bis(diphenylphosphino)methane (dppm), pinacolborane, CH₂Cl₂, r.t.; (vii) HCl, EtOAc, CHCl₃, r.t. or R-COOH, EDCI, HOBt, DMF, r.t. or R-COCl, TEA, CH₂Cl₂, N,N-dimethyl-4-aminopyridine (DMAP), r.t.; (viii) NH₄OAc, NaIO₄, acetone, H₂O, r.t., 48 h.

Scheme 14

Synthesis of the HDAC and proteasome dual target inhibitor 66. Reaction conditions: (i) (1) Boc-L-Phenylalanine, DMF, 0 °C; (2) TBTU, N-methylmorpholine (NMM), 16 h; (ii) HCl, EtOAc, 2 h; (iii) (1) Benzene-1,2-diamine, TBTU, DMF, 0 °C; (2) TEA, 8 h; (iv) LiOH, MeOH, 3 h; (v) (1) TBTU, DMF, 0 °C; (2) NMM, 8 h.

Scheme 15

Synthesis of the α-amido-β-triazolylethaneboronic acids 70 and 71. Reaction conditions: (i) NaN₃, H₂O, EtOAc, tetrabutylammonium iodide (TBAI); (ii) LiCHCl₂, −100 °C; (iii) LiN(SiMe₃)₂, THF, −100 °C to r.t., overnight; (iv) (1) MeOH, THF, −10 °C to r.t., 1 h; (2) RCOCl, −10 °C, 1 h; (v) H₂O, tert-BuOH, CuSO₄, 60 °C, 18 h; (vi) MeCN, HCl, n-hexane, r.t., 3 h.

Scheme 16

Synthesis of the cyclic boronic acid 75, inhibitor of serine β-lactamases and metallo enzymes. Reaction conditions: (i) Boc₂O, DMAP, CH₂Cl₂, r.t., 30 min; (ii) (1) Lithium diisopropylamide (LDA), THF, −78 °C, 1 h; (2) Boc₂O, DMAP, CH₂Cl₂, r.t., overnight; (iii) (1) TFA, CH₂Cl₂, r.t., 16 h; (2) acetone, TFA, trifluoroacetic anhydride (TFAA), 70 °C, overnight; (iv) acrylic acid, Pd(OAc)₂, tris(o-tolyl)phosphine (P(o-toly)₃), TEA, DMF, 100 °C, 14 h; (v) (1) Br₂, CHCl₃, 0 °C, 2 h; (2) TEA, DMF, 0 °C to r.t., 8 h; (vi) B₂((+)pinanediol)₂, PdCl₂(dppf), KOAc, dioxane, 60 °C, 2 h; (vii) CH₂N₂, Pd(OAc)₂, THF, −20 °C to r.t., 12 h; (viii) (1) column chromatography; (2) 3 N NaOH, dioxane, r.t., 30 min; (3) TFA, triethylsilane (TES), i-BuB(OH)₂, 0 °C to r.t., 30min.

Scheme 17

Synthesis of NorA efflux pump boronic acid inhibitors compounds 76 and 77. Reaction conditions: (i) (1) NaH, anhydrous THF, 0 °C to r.t., 30 min then reflux, 1 h; (2) 5-bromo-2-fluoropyridine, reflux, 12 h; (ii) (1) n-BuLi, anhydrous ether, −78 °C, 1 h; (2) B(OiPr)₃, −78 °C to r.t., 1 h; (3) 3 N HCl.

Scheme 18

Synthesis of the bis(indolyl)methane boronic acid derivative 80, a leucyl-tRNA synthetase inhibitor. Reaction conditions: (i) Fe(ox)–Fe₃O₄, H₂O, reflux.

Scheme 19

Synthesis of HIV-1 protease inhibitor 84 based on the drug darunavir. Reaction conditions: (i) TEA, 4-bromobenzenesulfonyl chloride, CH₂Cl₂, dry N₂ atmosphere, 0 °C, 16 h; (ii) KOAc, B₂pin₂, Pd(dppf)Cl₂–CH₂Cl₂, 1,4-dioxane, 80 °C, 24 h; (iii) (1) HCl, dioxane, r.t., 4 h; (2) TEA, 2,5-dioxopyrrolidin-1-yl ((3R,3S,6R)-hexahydrofuro[2,3b]furan-3-yl) carbonate, r.t., 16 h; (iv) acetone/H₂O, NaIO₄, NH₄OAc, r.t., 12 h.

Scheme 20

Synthesis of boronic acid derivatives 87–92 as IAV replication inhibitors. Reaction conditions: (i) Aromatic diamine, HCl, 2-ethoxyethanol, 100 °C, 2 h; (ii) 4-carboxyphenylboronic acid or 3-carboxyphenylboronic acid, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM), 2-ethoxyethanol, r.t., 18 h.

Scheme 21

Synthesis of NS5B inhibitor second generation derivative 100. Reaction conditions: (i) Methyl 5-fluoro-2-nitrobenzoate, Na₂CO₃, DMF, 70 °C, 72 h, (ii) palladium on carbon (Pd/C), THF/EtOH,, H₂, r.t., 24 h; (iii) (1) DMF, 60 °C, 5 min; (2) MeCN, HBr, NaNO₂, H₂O, 0 °C, 30 min; (3) CuBr, 50 °C, 30 min; (4) MeOH, LiBH₄/THF, −5 °C, 2 h; (5) THF, DIPEA, chloromethyl methyl ether (MOM-Cl), 50 °C, 18 h; (iv) (1) B₂Pin₂, Pd(dppf)Cl₂, 1,4-dioxane, N₂, 108 °C, 22 h; (2) THF, MeOH, HCl, 70 °C, 18 h.

Scheme 22

Synthesis of the flaviviral protease inhibitor 105 with boronic acid group. Reaction conditions: (i) (1) NMM, isobutyl chloroformate (IBCF); (2) (R)-4-bromo-1-((3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butan-1-amine, CH₂Cl₂, DIPEA, THF, −15 °C to r.t., overnight; (ii) (1) NaN₃, DMF, 100 °C, 1 h; (2) H₂, Pd/C, MeOH, r.t., overnight; (iii) bis-Boc-pyrazole-1-carboxamidine, DMAP, MeOH, r.t., 48 h; (iv) TFA, CH₂Cl₂, HCl, r.t., overnight; (v) PhB(OH)₂, H₂O, diethyl ether, HCl (aq.), r.t., overnight.